Functional requirement of telomere length and telomerase in the regulation of mitochondrial reactive oxygen species in cardiomyocyte health and disease

• Applicants: Professor Christian Bär, Ph.D.; Shambhabi Chatterjee, Ph.D.
• Subject Area: Cardiology, Angiology
• Term: since 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 341572583

Cardiovascular disease represents the most common cause of death globally and strongly correlates with age. Since the ageing population is expected to double in the next 30 years, this will significantly increase the share of age-associated disorders and cause a huge burden to the healthcare system. Ageing is a multifactorial process wherein DNA damage, telomere shortening and mitochondrial dysfunction are crucial events, which drive the process of ageing. DNA damage and metabolic defects are known to accompany all cardiovascular diseases. Additionally, telomere shortening as a source of DNA damage and cell senescence occurs throughout the lifespan of most mammals, due to the silencing of telomerase (TERT), which synthesizes and maintains telomeres. Several studies linked short telomeres to various cardiomyopathies where they can be uses as a marker for disease severity. We previously demonstrated that re-activation of TERT confers cardioprotection, which is at least partially attributed to extra-telomeric function of TERT within mitochondria. However, still little is known about the mechanistic interrelation of the mitochondrial dysfunction and telomere attrition in the context of cardiomyopathy. The major aim of this project is, therefore, to untangle both mechanisms and interactions of the TERT-telomere length-mitochondria axis in cardiovascular stress conditions and gain deeper insights into TERT’s potential to elicit cardiac regenerative responses. Mouse models (in vivo, ex vivo) and human induced pluripotent stem cell derived cardiomyocyte (in vitro) with different degrees of telomere shortening will be employed. In combination with viral and non-viral treatments for TERT re-activation, implemented as a therapeutic approach after myocardial infarction, the underlying mechanisms for cardioprotection and regeneration will be deciphered. The ultimate goal of these studies will be to combine state-of-the art models (neonatal MI, living myocardial slices, iPSC with CRISPR engineered telomeres) and techniques (high resolution STED microscopy, modRNA therapy) to devise novel pre-clinical approaches to target age-related cardiovascular diseases. In summary, this project aims at elucidating the connection between TERT-telomere length-metabolism in the context of cardiac damage and regeneration. It will lay a foundation for novel preventive and regenerative therapies for the heart.

• DFG Programme: Research Grants